Peptide based-compounds

Abstract

The invention relates to new peptide-based compounds and their use in diagnostic optical imaging techniques. More specifically the invention relates to the use of such peptide-based compounds as targeting vectors that bind to receptors associated with angiogenesis. The compounds are labelled with at least one cyanine dye reporter and may be used as contrast agents in optical imaging in diagnosis of angiogenesis-related diseases.

1. A compound comprising a peptidic vector and at least one cyanine dye, wherein the peptidic vector comprises the amino acid sequence X 3 -G-D, wherein the peptidic vector and the at least one cyanine dye are coupled, and wherein
 X 3  represents arginine or N-methylarginine, 
 G represents glycine, 
 D represents aspartic acid, 
 or a physiologically acceptable salt thereof. 
 
     
     
       2. A compound as claimed in  claim 1  wherein the at least one cyanine dye each comprises 2, 1 or no sulphonic acid moieties. 
     
     
       3. A compound as claimed in  claim 1  wherein the at least one cyanine dye is selected from the groups of carbacyanines, oxacyanines, thiacyanines and azacyanines. 
     
     
       4. A compound as claimed in  claim 1  wherein the at least one cyanine dye is a carbacyanine dye. 
     
     
       5. A compound as claimed in  claim 1  identified by the formula (VI a)
   A−Z   (VI a)
 
 wherein A is identified by the formula (VI b)
   R a —C(═O)-X 1 —X 2 —X 3 -G-D-X 4 —X 5 —X 6 —X 7    (VI b)
 
 
 and Z represents at least one cyanine dye, linked to one or more of X 1 , X 6  or X 7  of A, 
 the compound comprising two cyclising bridges, wherein, 
 X 3 , G and D defined in  claim 1 ; 
 R a  represents —(CH 2 ) n —or —(CH 2 ) n —C 6 H 4 — group, which forms part of a bridge binding to either of X 2 , X 4  or X 6 , wherein n represents a positive integer from 1 to 10, 
 X 1  represents a bond or 1, 2, 3, 4 or 5 amino acid residues, wherein at least one amino acid residue is optionally functionalised with a W 1  group, or said amino acid residue possesses a functional side-chain chosen from an acid or amine group, 
 X 2 , X 4  and X 6  independently represent an amino acid residue capable of forming a disulphide or thioether cyclising bridge, 
 X 5  represents a tyrosine, a phenylalanine, a 3-iodo-tyrosine or a naphthylalanine residue, and 
 X 7  represents a W 1  group or biomodifier moiety or is absent, wherein said biomodifier moiety comprises 1 to 10 units of a monodisperse polyethylene glycol (PEG) building block; 
 W 1  is a spacer moiety chosen from glutaric, succinic acid, or a polyethylene glycol group. 
 
     
     
       6. A compound as claimed in  claim 5  selected from any one of the formulas; 
       
         
           
           
               
               
           
         
         wherein R a , X 3 , G, D, X 5 , and X 7  are as defined in  claim 5  and wherein 
         X′ 1  comprises an amino acid residue with a functional side-chain chosen from an acid or amine group, 
         X′ 2 , X′ 4  and X′ 6  represent amino acid residues forming a disulphide or a thioether bond, 
         W 1  is a spacer moiety as defined in  claim 5  or is absent, 
         h is a positive integer of 1 or 2, 
         and wherein at least one of the Z groups is present, Z representing a cyanine dye. 
       
     
     
       7. A compound of formula VII as claimed in  claim 6  wherein R a  represents —(CH 2 )—. 
     
     
       8. A compound of formula VII as claimed in  claim 6  wherein X′ 1  represents an amino acid residue with a functional side-chain chosen from an acid or amine group, the amino acid being selected from aspartic acid, glutamic acid, homolysine, lysine or diaminopropionic acid. 
     
     
       9. A compound of formula VII as claimed in  claim 6  wherein X′ 2 , X′ 4  and X′ 6  independently represent a cysteine or homocysteine residue. 
     
     
       10. A compound of formula VII as claimed in  claim 6  wherein X 3  represents arginine. 
     
     
       11. A compound of formula VII as claimed in  claim 6  wherein X 5  represents phenylalanine, tyrosine, 3-iodo-tyrosine or naphthylalanine. 
     
     
       12. A compound of formula VII as claimed in  claim 6  wherein X 7  comprises 1-10 units of a monodisperse PEG building block or is absent. 
     
     
       13. A compound as claimed in  claim 6  wherein the cyanine dyes Z are linked to one or more of X′ 1 , W 1 , X 6  or X 7  via an amide, sulphonamide or a thioether linkage. 
     
     
       14. A pharmaceutical composition comprising an effective amount of a compound as claimed in  claim 1 , together with one or more pharmaceutically acceptable adjuvants, excipients or diluents. 
     
     
       15. An optical imaging contrast agent which comprises the compound as claimed in  claim 1 . 
     
     
       16. A method of optical imaging of a human or animal body comprising administering a contrast agent as defined in  claim 15  to said body, and generating an image of at least a part of said body to which said contrast agent has distributed. 
     
     
       17. A method of monitoring the effect of treatment of a human or animal body with a drug, said method comprising administering to said body a compound as claimed in  claim 1  a composition as claimed in  claim 14 , and detecting the uptake of said compound or composition by cell receptors via optical imaging, said administration and detection optionally being effected before, during and after treatment with said drug.